Repurposing Chlorpromazine in the Treatment of Glioblastoma

Summary

This study evaluates the addition of chlorpromazine to the first-line therapeutic protocol, i.e. maximal well-tolerated surgical resection followed by radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide, in newly diagnosed glioblastoma multiforme patients carrying a hypo-methylated O6-methylguanine-DNA-methyltransferase (MGMT) gene

Timeline

Start

2019-12-15

Primary completion

2022-06-15

Completion

2022-12-15

Publications

• Background Cohen BM, Lipinski JF. In vivo potencies of antipsychotic drugs in blocking alpha 1 noradrenergic and dopamine D2 receptors: implications for drug mechanisms of action. Life Sci. 1986 Dec 29;39(26):2571-80. doi: 10.1016/0024-3205(86)90111-6.
• Background Nordenberg J, Fenig E, Landau M, Weizman R, Weizman A. Effects of psychotropic drugs on cell proliferation and differentiation. Biochem Pharmacol. 1999 Oct 15;58(8):1229-36. doi: 10.1016/s0006-2952(99)00156-2.
• Background Pinheiro T, Otrocka M, Seashore-Ludlow B, Rraklli V, Holmberg J, Forsberg-Nilsson K, Simon A, Kirkham M. A chemical screen identifies trifluoperazine as an inhibitor of glioblastoma growth. Biochem Biophys Res Commun. 2017 Dec 16;494(3-4):477-483. doi: 10.1016/j.bbrc.2017.10.106. Epub 2017 Oct 21.
• Background Lee MS, Johansen L, Zhang Y, Wilson A, Keegan M, Avery W, Elliott P, Borisy AA, Keith CT. The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action. Cancer Res. 2007 Dec 1;67(23):11359-67. doi: 10.1158/0008-5472.CAN-07-2235.
• Background Shin SY, Lee KS, Choi YK, Lim HJ, Lee HG, Lim Y, Lee YH. The antipsychotic agent chlorpromazine induces autophagic cell death by inhibiting the Akt/mTOR pathway in human U-87MG glioma cells. Carcinogenesis. 2013 Sep;34(9):2080-9. doi: 10.1093/carcin/bgt169. Epub 2013 May 20.
• Background Barygin OI, Nagaeva EI, Tikhonov DB, Belinskaya DA, Vanchakova NP, Shestakova NN. Inhibition of the NMDA and AMPA receptor channels by antidepressants and antipsychotics. Brain Res. 2017 Apr 1;1660:58-66. doi: 10.1016/j.brainres.2017.01.028. Epub 2017 Feb 3.
• Background Venkatesh HS, Morishita W, Geraghty AC, Silverbush D, Gillespie SM, Arzt M, Tam LT, Espenel C, Ponnuswami A, Ni L, Woo PJ, Taylor KR, Agarwal A, Regev A, Brang D, Vogel H, Hervey-Jumper S, Bergles DE, Suva ML, Malenka RC, Monje M. Electrical and synaptic integration of glioma into neural circuits. Nature. 2019 Sep;573(7775):539-545. doi: 10.1038/s41586-019-1563-y. Epub 2019 Sep 18.
• Background Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, Korber C, Kardorff M, Ratliff M, Xie R, Horstmann H, Messer M, Paik SP, Knabbe J, Sahm F, Kurz FT, Acikgoz AA, Herrmannsdorfer F, Agarwal A, Bergles DE, Chalmers A, Miletic H, Turcan S, Mawrin C, Hanggi D, Liu HK, Wick W, Winkler F, Kuner T. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature. 2019 Sep;573(7775):532-538. doi: 10.1038/s41586-019-1564-x. Epub 2019 Sep 18.
• Background Zeng Q, Michael IP, Zhang P, Saghafinia S, Knott G, Jiao W, McCabe BD, Galvan JA, Robinson HPC, Zlobec I, Ciriello G, Hanahan D. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature. 2019 Sep;573(7775):526-531. doi: 10.1038/s41586-019-1576-6. Epub 2019 Sep 18.
• Background Caragher SP, Shireman JM, Huang M, Miska J, Atashi F, Baisiwala S, Hong Park C, Saathoff MR, Warnke L, Xiao T, Lesniak MS, James CD, Meltzer H, Tryba AK, Ahmed AU. Activation of Dopamine Receptor 2 Prompts Transcriptomic and Metabolic Plasticity in Glioblastoma. J Neurosci. 2019 Mar 13;39(11):1982-1993. doi: 10.1523/JNEUROSCI.1589-18.2018. Epub 2019 Jan 16.
• Pace A, Lombardi G, Villani V, Benincasa D, Abbruzzese C, Cestonaro I, Corra M, Padovan M, Cerretti G, Caccese M, Silvani A, Gaviani P, Giannarelli D, Ciliberto G, Paggi MG. Efficacy and safety of chlorpromazine as an adjuvant therapy for glioblastoma in patients with unmethylated MGMT gene promoter: RACTAC, a phase II multicenter trial. Front Oncol. 2023 Dec 14;13:1320710. doi: 10.3389/fonc.2023.1320710. eCollection 2023.
• Matteoni S, Matarrese P, Ascione B, Buccarelli M, Ricci-Vitiani L, Pallini R, Villani V, Pace A, Paggi MG, Abbruzzese C. Anticancer Properties of the Antipsychotic Drug Chlorpromazine and Its Synergism With Temozolomide in Restraining Human Glioblastoma Proliferation In Vitro. Front Oncol. 2021 Feb 26;11:635472. doi: 10.3389/fonc.2021.635472. eCollection 2021.

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Indications